Materials and methods for improving alcohol metabolism and alleviating the effects of hangovers

ABSTRACT

The subject invention provides materials and methods for improving alcohol metabolism in animals. In a preferred embodiment, the invention provides methods for increasing the ability of people to consume alcohol while reducing hangovers or other effects of intoxication. Specifically exemplified herein is the use of a cysteamine compound to reduce the adverse effects of alcohol consumption. For example, the undesirable and unpleasant symptoms association with hangovers can be reduced through consumption, according to the subject invention, of cysteamine hydrochloride.

CROSS-REFERENCE TO A RELATED APPLICATION

This application is a continuation application of co-pending applicationSer. No. 13/596,649, filed Aug. 28, 2012, which claims priority toapplication Ser. No. 12/890,890, filed Sep. 27, 2010, now U.S. Pat. No.8,258,187; which is a continuation application of U.S. application Ser.No. 10/982,160, filed Nov. 5, 2004, now U.S. Pat. No. 7,803,843; whichclaims the benefit of provisional patent application Ser. No.60/523,451, filed Nov. 19, 2003, all of which are hereby incorporated byreference in their entirety.

BACKGROUND OF INVENTION

Metabolism is the body's process of converting ingested substances toother compounds. Metabolism involves a number of processes, one of whichis referred to as oxidation. Through oxidation, alcohol is detoxifiedand removed from the blood, preventing the alcohol from accumulating andharming cells and organs. Until all the alcohol consumed has beenmetabolized, it is distributed throughout the body, affecting the brain,liver, and other tissues and organs.

When alcohol is consumed, it is absorbed into the blood from the stomachand intestines. Alcohol is then metabolized through the action ofenzymes. Specifically, in the liver, alcohol dehydrogenase (ADH)mediates the conversion of alcohol to acetaldehyde.

Acetaldehyde is then quantitatively oxidized to acetic acid in thepresence of aldehyde dehydrogenase (ALDH) and nicotinamide-adeninedinucleotide (NAD).

Acetate is eventually metabolized to carbon dioxide and water.

Alcohol also is metabolized in the liver by cytochrome P450IIE1(CYP2E1), which may be increased after chronic drinking.

The microsomol ethanol oxidizing system (MEOS) is also involved inalcohol metabolism. Ethanol induces MEOS activity while lowering ALDHactivity (Lebsack, M. E., E. R. Gordon, and C. S. Lieber, 1981 “Effectof chronic ethanol consumption on aldehyde dehydrogenase activity in thebaboon” Biochem. Pharmacol. 30:2273-2277); therefore, acetaldehyde andreactive oxygen species accumulate upon chronic or high consumption ofethanol. These toxic molecules can cause cell injury through lipidperoxidation, protein inactivation and DNA damage.

The liver can metabolize only a certain amount of alcohol per hour. Therate of alcohol metabolism depends, in part, on the amount ofmetabolizing enzymes in the liver, which varies among individuals andhas genetic determinants. In general, after the consumption of onestandard drink, the amount of alcohol in the drinker's blood (bloodalcohol concentration, or BAC) peaks within 30 to 45 minutes. Alcohol ismetabolized more slowly than it is absorbed. Since the metabolism ofalcohol is slow, alcohol can accumulate in the body and intoxicationoccurs.

A number of factors influence the process of alcohol absorption,including the presence of food and the type of food in thegastrointestinal tract when alcohol is consumed. The rate at whichalcohol is absorbed depends on how quickly the stomach empties itscontents into the intestine. For example, the higher the dietary fatcontent, the more time this emptying will require and the longer theprocess of absorption will take.

Thus, dietary components can affect ethanol absorption and metabolism.Ethanol absorption is controlled mainly by gastric emptying, because theprimary region of ethanol absorption is the small intestine. Vegetableoils such as soybean oil and coconut oil delay the elimination rate ofgastric ethanol and lessen the increase in plasma ethanol concentration.Moreover, because ethanol-metabolizing enzymes such as ADH, ALDH andMEOS contribute to the clearance of ethanol and toxic acetaldehyde,components that stimulate these enzyme activities are expected toameliorate alcohol toxicity. For example, sesamin and garlic stimulateethanol metabolism, especially acetaldehyde clearance (Yang, Z, Y. Suwa,K. Hirai et al. 1995, “Effects of sesamin on ethanol-induced musclerelaxation” J. Jpn. Soc. Nutr. Food Sci. 48:103-108; and Kishimoto, R.,M. Ueda, H. Yoshinaga, K. Goda, S.-S. Park (1999) “Combined effects ofethanol and garlic on hepatic ethanol metabolism in mice” J. Nutr. Sci.Vitaminol. 45:275-286).

There are also differences in alcohol metabolism based on gender. Womenabsorb and metabolize alcohol differently from men. Women tend to havehigher BAC's after consuming the same amount of alcohol as men and aremore susceptible to alcoholic liver disease, heart muscle damage, andbrain damage. The difference in BAC's between women and men has beenattributed to women's smaller amount of body water. An additional factorcontributing to the difference in BAC's may be that women have loweractivity of the alcohol metabolizing enzyme ADH in the stomach, causinga larger proportion of the ingested alcohol to reach the blood.

Alcohol consumption and metabolism can have very important healthconsequences. For example, although moderate doses of alcohol added tothe diets of lean men and women do not seem to lead to weight gain, somestudies have reported weight gain when alcohol is added to the diets ofoverweight persons.

Also, alcohol metabolism alters the balance of reproductive hormones inmen and women. In men, alcohol metabolism contributes to testicularinjury and impairs testosterone synthesis and sperm production.Prolonged testosterone deficiency may contribute to feminization inmales, for example, breast enlargement.

In women, alcohol metabolism may contribute to increased production of aform of estrogen called estradiol (which contributes to increased bonedensity and reduced risk of coronary artery disease) and to decreasedestradiol metabolism, resulting in elevated estradiol levels.

Chronic heavy drinking appears to activate the enzyme CYP2E1, which maybe responsible for transforming the over-the-counter pain relieveracetaminophen (TYLENOL) into chemicals that can cause liver damage.Alcohol consumption affects the metabolism of a wide variety of othermedications, increasing the activity of some and diminishing theactivity, thereby decreasing the effectiveness, of others.

In addition to possible life-threatening drug interactions and long-termpotential deleterious effects of alcohol intoxication on various organsand systems, alcohol consumption and intoxication can result inshort-term, but very unpleasant or inconvenient, effects. These effects,commonly collectively referred to as a “hangover,” can include, forexample, headaches, nausea, and fatigue. Many hangover “remedies” havebeen proposed with mixed success. See, for example, U.S. Pat. Nos.6,221,358 and 6,485,758.

The problems associated with alcohol intoxication and hangovers can beparticularly acute for individuals having a genetic variation thatreduces their natural ability to metabolize and detoxify alcohol. Asianpopulations (including, for example Chinese and Japanese) inheritprimarily the active ADH2 variant whereby alcohol is rapidly convertedto acetaldehyde, but they also primarily inherit the inactive AIDH22gene whereby the toxic acetaldehyde is not converted to acetate, so itaccumulates in the blood. A systemic adverse reaction ensues.

Soybeans are consumed in Japan as part of an ordinary diet. Tofu and“edamame,” boiled fresh soybeans, are popular snacks to consume withalcohol, although few reports have been published about the effect ofsoy products on ethanol consumption. However, isoflavones prepared fromthe crude extract of Pueraria lobata are used as a traditional medicinefor anti-inebriation and suppress alcohol intake by alcohol-preferringrats (Lin, R. C., S. Guthrie, C. Y. Xie et al. 1996 “Isoflavonoidcompounds extracted from Pueraria lobata suppress alcohol preference ina pharmacogenetic rat model of alcoholism” Alcohol Clin. Exp. Res.20:659-663; and Overstreet, D. H., Y. W. Lee, A. H. Rezvani et al. 1996“Suppression of alcohol intake after administration of the Chineseherbal medicine, NPI-028, and its derivatives” Alcohol Clin. Exp. Res.20:221-227). The major components of the extract, daidzin and daidzein,are inhibitors in vitro of mitochondrial low K_(m) ALDH (Keung, W.-M.and B. L. Vallee, 1993, “Daidzin: a potent, selective inhbitor of humanmitochondrial aldehyde dehydrogenase” Proc. Natl. Acad. Sci. USA90:1247-1251) and ADH (W. M. Keung, 1993, “Biochemical studies of a newclass of alcohol dehydrogenase inhibitors from Raix puerarae” AlcoholClin. Exp. Res. 17:1254-1260), whereas intragastric or intraperitonealinjection of daidzin to rodents does not affect these enzyme activities(Keung, W.-M., O. Lazo, L. Kunze, B. L. Vallee, 1995 “Daidzin suppressesethanol consumption by Syrian golden hamsters without blockingacetaldehyde metabolism” Pro. Natl. Acad. Sci. USA 92:8990-8993; andXie, C. I., R. C. Lin, V. Antony et al., 1994 “Daidzin, an antioxidantisoflavonoid, decreases blood alcohol levels and shortens sleep timeinduced by ethanol intoxication” Alcohol Clin. Exp. Res. 18:1443-1447).

Kano et al., who studied the effects of soymilk (SM) products, includingfermented soymilk (FSM), on ethanol absorption and metabolism (“SoymilkProducts Affect Ethanol Absorption and Metabolism in Rats during Acuteand Chronic Ethanol Intake,” Kano, M., F. Ishikawa, S. Matsubara, H.Kikuchi-Hayakawa and Y. Shimakawa, Yakult Central Institute forMicrobiological Research, Yaho 1796, Kunitachi, Tokyo 186-8650, Japan,J. Nutr. 132:238-244, 2002), found that soy products inhibit ethanolabsorption and enhance ethanol metabolism, and that isoflavones may bethe active factors. Soy isoflavones have antioxidative activity, actingto reinforce the system. It was also found that soy products improveparameters of cell injury due to chronic ethanol exposure and thatsoymilk products contribute to the suppression of ethanol-induced cellinjury.

Soy products appear to alter ethanol metabolism through inhibition ofcytochrome P₄₅₀ (CYP)2E1 in MEOS. Chae et al. (Chae, Y.-H., C. B.Marcus, D. K. Ho et al., 1991, “Effects of synthetic and naturallyoccurring flavonoids on benzojalpyrene metabolism by hepatic microsomesprepared from rats treated with cytochrome P-450 inducers” Can. Lett.60:15-24) reported that genistein is a potent inhibitor of CYP1A1 and/orCYP1A2 induced by β-naphthoflavone, and Ronis et al. (Ronis, M. J., J.C. Rowlands, R. Hakkak and T. M. Badger, 1999, “Altered expression andglucocorticoid-inducibility of hepatic CYP3A and CYP2B enzymes in malerats fed diets containing soy protein isolate” J. Nutr. 129:1958-1965)found that soy protein increases the dexamethasone-induced mRNAexpression of hepatic CYP3A2 compared with casein, suggesting arelationship between soy components and the cytochrome P₄₅₀ system,although the effects of soy components on CYP2E1 are not yet known.Thus, the consumption of soy products contributes to the prevention ofethanol-induced liver injury through enhancement of ethanol metabolismand the antioxidation system.

Despite the availability of certain strategies for reducing hangovers,there remains a great need for better approaches to enhance alcoholmetabolism and detoxification, especially for certain Asians, andothers, who have a reduced ability to metabolize alcohol into non-toxiccompounds.

BRIEF SUMMARY

The subject invention provides materials and methods for improvingalcohol metabolism in animals. In a preferred embodiment, the inventionprovides methods for increasing the ability of people to consume alcoholwhile reducing hangovers or other effects of intoxication.

Specifically exemplified herein is the use of a cysteamine compound toreduce the adverse effects of alcohol consumption. For example, theundesirable and unpleasant symptoms association with hangovers can bereduced through consumption, according to the subject invention, ofcysteamine hydrochloride.

Further advantages of the subject invention include effective protectionof the liver due to a higher rate of detoxification of alcohol.

A further aspect of the invention is the provision of compositions,which comprise cysteamine hydrochloride, that can be used according tothe subject invention to ameliorate the adverse and toxic effects ofalcohol consumption.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a decrease in plasma ethanol concentration achieved throughthe practice of the subject invention.

FIG. 2 shows an increase alcohol dehydrogenase (ADH) activity achievedthrough the practice of the subject invention.

FIG. 3 shows an increase in aldehyde dehydrogenase (ALDH) activityachieved through he practice of the subject invention.

FIG. 4 shows a metabolic pathway of cysteamine.

FIG. 5 shows cysteamine as a constituent of co-enzyme A.

DETAILED DISCLOSURE

The subject invention provides materials and methods for improvingalcohol metabolism and detoxification in animals. In preferredembodiments, the invention provides methods and compositions forincreasing the ability of people to consume alcohol while reducinghangovers or other effects of intoxication.

The symptoms of a hangover can include headache, dehydration,congestion, stomach pains, and diarrhea. The hangover is caused by thebreakdown of alcohol in the liver especially acetaldehyde which has beenfound to be highly toxic.

Specifically exemplified herein is the use of cysteamine hydrochloride(and/or analogs, derivatives and prodrugs thereof) to reduce the adverseeffects of alcohol consumption. For example, the undesirable andunpleasant symptoms association with hangovers can be reduced throughconsumption, according to the subject invention, of a cysteaminecompound.

Further advantages of the subject invention include effective protectionof the liver due to a higher rate of detoxification of alcohol.

As used herein, reference to a “cysteamine compound” includes thevarious cysteamine salts (such as cysteamine hydrochloride andcysteamine phosphate) as well as prodrugs of cysteamine that can, forexample, be readily metabolized in the body to produce cysteamine. Alsoincluded within the scope of the subject invention are analogs ofcysteamine which have the ability as described herein to reduce theeffects of hangovers and/or increase acetaldehyde dehydrogenaseactivity. Various analogs, derivatives, conjugates, and metabolites ofcysteamine are well known and readily used by those skilled in the artand include, for example, compounds, compositions and methods ofdelivery as set forth in U.S. Pat. Nos. 6,521,266; 6,468,522; and5,714,519.

In one embodiment of the subject invention, the advantages ofcysteamine, as set forth herein, can be achieved by promoting theendogenous production of cysteamine through natural metabolic processsuch as through the action of co-enzyme A or as a metabolite of cysteine(see FIGS. 4 and 5). This can be achieved by, for example, theadministration of pantothenic acid.

One method to increase levels of cysteamine involves pantothenic acid.Pantothenic acid is a naturally occurring vitamin that is converted inmammals to coenzyme A, a substance vital to many physiologicalreactions. Cysteamine is a component of coenzyme A, and increasingcoenzyme A levels results in increased levels of circulating cysteamine.Alkali metal salts, such as magnesium phosphate tribasic and magnesiumsulphite (Epsom salts), enhance formation of coenzyme A. Furthermore,breakdown of coenzyme A to cysteamine is enhanced by the presence of areducing agent, such as citric acid. Thus, the combination ofpantothenic acid and alkali metal salts results in increased coenzyme Aproduction and, concomitantly, cysteamine.

In one embodiment, the subject invention provides methods for loweringethanol concentrations in the plasma of individuals who have consumedalcoholic beverages. This is achieved, at least in part, by increasingalcohol dehydrogenase (ADH) activity in the liver. Thus, individuals whotake a cysteamine compound in accordance with the subject invention canimprove the ADH activity and, advantageously, lower the plasmaconcentration of ethanol.

A further advantage obtained through the practice of the subjectinvention is an increase in acetaldehyde dehydrogenase (ALDH) activity.This, too, helps enhance the metabolism and detoxification of ethanol.

Accordingly, through the practice of the subject invention, the activityof important enzymes can be enhanced, plasma levels of ethanoldecreased, and the negative effects of hangovers reduced or eliminated.A further advantage is a decreased risk to the liver and other organsfrom ethanol and/or toxic intermediate metabolites in the metabolism ofethanol.

Advantageously, the subject invention also provides compositions andmethods that can reduce the effects of hangovers and/or speed the timefor recovery for an individual after they have ingested large quantitiesof alcohol. The term “alcohol” as used herein refers to ethyl alcoholand “alcoholic beverages” and refers to spirits or blends that areintended for human consumption. In a preferred embodiment, thecysteamine compound is formulated in a patentable and easily consumedoral formulation such as a pill, lozenge, tablet, gum, beverage, etc.The consumption is then taken at, shortly before, or after, the time ofalcohol consumption.

The present application is also directed to a kit having at least onecompartment, wherein a first compartment comprises a compositioncomprising an effective amount of a cysteamine compound of the subjectinvention. In certain embodiments where the kit has more than onecompartment, a second compartment includes at least one item appropriatefor an individual who has, or will, consume alcohol.

The additional item, which would typically be separatelycompartmentalized within the kit, may be either humorous or functional,or both. The additional item may be, for example, an item that will helpalleviate hangover effects. Such items include, but are not limited to,analgesics, supplements, food items, compositions to relieve upsetstomach, and caffeine. Accordingly, the additional item may be selectedfrom the following: a supplement composition comprising vitamins (suchas vitamins B, E, and C) and minerals (such as potassium); a nutritionalbar such as a protein bar; a composition comprising acetaminophen; and acomposition comprising a stimulant such as caffeine, ephedra, or mahuang.

Examples of humorous items that can be included in a kit of the subjectinvention include, but are not limited to, items relating to sexualperformance (such as VIAGRA (Pfizer), toy handcuffs, etc.); contactinformation for taxis or other appropriate services; and items useful inpromoting sleep (such as earplugs, blindfold, etc.).

In certain embodiments, the composition comprising a cysteamine compoundof the invention may be provided in a container (for example, adisposable packet; a bottle with a childproof cap; a cellophane bag,etc.). The kit would also typically contain instructions.

Materials and Methods Experiment Design:

1. Select 30 Wistar male rat (10 weeks old, 300-350 g), divided into 3groups. Group one is negative control (no ethanol and CT2000 treatment),group two is control (treated with ethanol only); Group three istreatment group (treated with both ethanol and CT2000).

2. 99.9% Ethanol (Analytical Grade) was diluted to 60% for usage.

3. CT2000 can be obtained from Shanghai Walcom Bio-Chem Co. Ltd. whichis located at T15-3, Ground Floor, No. 999 Ning Qiao Road, Pudong,Shanghai, China. CT2000 is composed of about 37% cysteaminehydrochloride, while the rest is carrier e.g., starch, microcrystallinecellulose, sodium alignate etc.

Treatment Method:

1. Before the experiment, the rats were left in the cage for 7 days forthem to adapt to the environment. Before the ethanol treatment, the ratswere not fed for 16 hours overnight. In the next morning at 11:00 am,the negative control and control groups were treated with 1 ml salineper rat, while the treatment group was treated with CT2000 at a dosageof 20 mg/kg body weight.

-   -   One hour later, the negative control was treated with glucose        4.8 g/kg body weight. While the control group and the treatment        group were treated with ethanol 2.7 g/kg bw.

2. Sampling: Two hours after administering ethanol, the rats weresacrificed and blood and liver were collected and stored in liquidnitrogen under −70° C.

3. Sample Analysis

1. Plasma ethanol was measured by F-Kits Ethanol. Ethanol can be readilymeasured by those skilled in the art using, for example, standard assayssuch as those available from Boehringer Mannheim (Roche)

2. Liver alcohol dehydrogenase and acetaldehyde dehydrogenase weremeasured according to the methods described in “Soymilk Products AffectEthanol Absorption and Metabolism in Rats during Acute and ChronicEthanol Intake,” Kano, M., F. Ishikawa, S. Matsubara, H.Kikuchi-Hayakawa and Y. Shimakawa, Yakult Central Institute forMicrobiological Research, Yaho 1796, Kunitachi, Tokyo 186-8650, Japan,J. Nutr. 132:238-244, 2002. The procedures were simplified by normalizethe value by the weight of liver instead of the protein level. Inaddition, the activity measured was expressed as optical density (OD)value without converting into the NADH quantities.

Following are examples which illustrate procedures for practicing theinvention. These examples should not be construed as limiting. Allpercentages are by weight and all solvent mixture proportions are byvolume unless otherwise noted.

Example 1 Reduction in Plasma Ethanol Level

As shown in Table 1 and FIG. 1, use of CT2000 results in a reduction inplasma ethanol levels after ingestion of ethanol.

TABLE 1 Negative Control Control Treatment Average 0 0.66 0.34 SD 0 0.340.15 Note: One tail, Control vs Treatment, n = 6 per group; also,negative control showed negative figures which were regarded as zero.

Example 2 Alcohol Dehydrogenase (ADH) Activity in Liver

As shown in Table 2 and FIG. 2, use of CT2000 results in an increase inADH activity after ingestion of ethanol.

TABLE 2 Negative Control Control Treatment Average 0.1 0.38 0.53 SD0.023 0.0075 0.068 Note: One tail, Control vs Treatment, n = 6 per group

Example 3 Alcohol Acetaldehyde (ALDH) Activity in Liver

As shown in Table 3 and FIG. 3, use of CT2000 results in an increase inALDH activity after ingestion of alcohol.

TABLE 3 Negative Control Control Treatment Average 0.91 1.093 1.23 SD0.069 0.15 0.069 Note: One tail, Control vs Treatment, n = 6 per group

Example 4 Uses, Formulations, and Administrations

Administration of the compositions of the subject invention can beaccomplished by any suitable method and technique presently orprospectively known to those skilled in the art.

The compounds of the subject invention can be formulated according toknown methods for preparing pharmaceutically useful compositions.Formulations are described in detail in a number of sources which arewell known and readily available to those skilled in the art. Forexample, Remington's Pharmaceutical Science by E. W. Martin describesformulations which can be used in connection with the subject invention.In general, the compositions of the subject invention will be formulatedsuch that an effective amount of the bioactive compound(s) is combinedwith a suitable carrier in order to facilitate effective administrationof the composition.

In accordance with the invention, compositions comprising, as an activeingredient, an effective amount of the compounds and one or morenon-toxic, pharmaceutically acceptable carrier or diluent. Examples ofsuch carriers for use in the invention include ethanol, dimethylsulfoxide, glycerol, silica, alumina, starch, and equivalent carriersand diluents.

To provide for the administration of such dosages for the desiredtherapeutic treatment, compositions of the invention will typicallycomprise between about 0.1% and 45%, of the total composition includingcarrier or diluent. The dosage used can be varied based upon the age,weight, health, or the gender of the individual to be treated.

The compositions of the invention can be used in a variety of forms,e.g., tablets, capsules, pills, powders, aerosols, granules, and oralsolutions or suspensions and the like containing the indicated suitablequantities of the active ingredient. Such compositions are referred toherein generically as “pharmaceutical compositions.” Typically, they canbe in unit dosage form, namely, in physically discrete units suitable asunitary dosages for human consumption, each unit containing apredetermined quantity of active ingredient calculated to produce thedesired therapeutic effect in association with one or morepharmaceutically acceptable other ingredients, e.g., diluent or carrier.

All patents, patent applications, and publications referred to or citedherein are incorporated by reference in their entirety, including allfigures and tables, to the extent they are not inconsistent with theexplicit teachings of this specification.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication.

We claim:
 1. A method for increasing acetaldehyde dehydrogenase activityin a person in need of such increase wherein said method comprisesadministering to said person an effective amount of cysteamine, or asalt thereof.
 2. The method, according to claim 1, wherein saidcysteamine salt is cysteamine hydrochloride.
 3. The method, according toclaim 1, wherein said person is lacking one or more enzymes involved inthe metabolism and detoxification of alcohol.
 4. The method, accordingto claim 1, wherein said cysteamine or salt thereof is taken orally. 5.A method for increasing alcohol dehydrogenase activity in a person inneed of such increase wherein said method comprises administering tosaid person an effective amount of cysteamine or a salt thereof.
 6. Themethod, according to claim 5, wherein said cysteamine salt is cysteaminehydrochloride.
 7. The method, according to claim 5, wherein said personis lacking one or more enzymes involved in the metabolism anddetoxification of alcohol.
 8. The method, according to claim 5, whereinsaid cysteamine or salt thereof is taken orally.
 9. A kit for reducingadverse effects associated with alcohol consumption, said kit comprisingat least one compartment, wherein a first compartment comprises acomposition comprising an effective amount of cysteamine or a saltthereof; and at least one additional item that is appropriate for aperson who has consumed alcohol.
 10. The kit, according to claim 9,wherein said at least one additional item is helpful in alleviatinghangover effects.
 11. The kit, according to claim 10, wherein said atleast one additional item is selected from the group consisting of: ananalgesic, a supplement, a food item, a composition to relieve upsetstomach, and a stimulant.